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Serum Cu, Zn and IL–1β Levels May Predict Fetal Miscarriage Risk After IVF Cycles: A Nested Case–Control Study

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Abstract

To explore the association between serum-related indicators (levels of inflammatory cytokines and essential trace elements) and miscarriage risk among infertile women undergoing assisted reproductive techniques (ART) on the 14th day after embryo transfer, and to develop and establish a multivariable algorithm model that might predict pregnancy outcome. According to a nested case–control study design, a total of 100 miscarriage cases and 100 live birth controls were included in this study, and women in both groups were infertile and have underwent in vitro fertilization (IVF). Pregnancy tests were performed and serum levels of five essential trace elements (vanadium (V), copper (Cu), zinc (Zn), selenium (Se) and molybdenum (Mo)) and five inflammatory cytokines (interleukin–1β (IL–1β), IL–6, IL–8, IL–10 and tumor necrosis factor–α (TNF–α)) of the participants were measured on the 14th day after embryo transfer. The serum levels of five inflammatory cytokines were determined by multiple magnetic bead enzyme immunity analyzer; and the serum concentrations of five elements were determined simultaneously by inductively coupled plasma‒mass spectrometry (ICP ‒ MS). The logistic regression was used to evaluate the relationship between these serum indices and miscarriage risk among women undergoing ART, and a predictive model of pregnancy outcome based on these indices was established. The levels of IL–10, IL–1β and TNF–α of infertile women in the live birth group were significantly higher than those in the miscarriage group (p = 0.009, p < 0.001, p = 0.006), and the levels of V, Cu, Zn and Se of infertile women in the live birth group were also significantly higher than those in the miscarriage group (all p < 0.001). Through logistic regression analyses, we found that serum levels of IL–1β, TNF–α, V, Cu, Zn and Se were significantly and negatively associated with miscarriage risk. Different combination prediction models were generated according to the results of logistic regression analyses, and the combination of IL–1β, Cu and Zn had the best prediction performance. The area under the curve (AUC) was 0.776, the sensitivity of the model was 60% and the specificity was 84%. In conclusion, the serum-related indicators of women undergoing ART on the 14th day after embryo transfer, including the inflammatory cytokines such as IL–1β and TNF–α and the essential trace metal elements such as V, Cu, Zn and Se, were negatively correlated with miscarriage risk. A multivariate algorithm model to predict pregnancy outcome among women undergoing ART was established, which showed that IL–1β, Cu and Zn might synergistically predict pregnancy outcome.

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Data Availability

All data generated or analysed during this study are included in this published article (and its supplementary information files).

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Acknowledgements

The authors thank all the medical staff in the First Afflicted Hospital of Anhui Medical University in Anhui, China for their work in recruiting subjects and collecting specimens. The authors are grateful to the Scientific Research Center in Preventive Medicine, School of Public Health, Anhui Medical University for the technical support in our experiment.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC–82173532, NSFC–U20A20350, NSFC–81971455, NSFC–81871216 and NSFC–81601345), the Excellent Young Talents Fund Program of Higher Education Institutions of Anhui Province (gxyq2021173), the Postdoctoral Research Foundation of China (2021M700181), the University Natural Science Research Project of Anhui Province (KJ2020A0203), the National Key Research and Development Program (2018YFC1004201, 2016YFC1000204).

Author information

Author notes

  1. Yuan Hu, Dongyang Zhang, Qing Zhang, and Tao Yin contributed equally to this work.

Authors and Affiliations

  1. School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Yuan Hu, Dongyang Zhang, Tingting Jiang, Shitao He, Mengzhu Li, Fangbiao Tao, Yanli Ji & Chunmei Liang

  2. Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China

    Tao Yin, Xinyu Yue, Guiying Luo, Yunxia Cao, Dongmei Ji & Chunmei Liang

  3. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Yuan Hu, Dongyang Zhang, Tao Yin, Tingting Jiang, Shitao He, Mengzhu Li, Xinyu Yue, Guiying Luo, Fangbiao Tao, Yunxia Cao, Dongmei Ji, Yanli Ji & Chunmei Liang

  4. NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China

    Yuan Hu, Dongyang Zhang, Tao Yin, Tingting Jiang, Shitao He, Mengzhu Li, Xinyu Yue, Guiying Luo, Fangbiao Tao, Yunxia Cao, Dongmei Ji, Yanli Ji & Chunmei Liang

  5. Anhui Province Key Laboratory of Reproductive Health and Genetics, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Yuan Hu, Dongyang Zhang, Tao Yin, Tingting Jiang, Shitao He, Mengzhu Li, Xinyu Yue, Guiying Luo, Fangbiao Tao, Yunxia Cao, Dongmei Ji, Yanli Ji & Chunmei Liang

  6. Anhui Provincial Engineering Research Center of Biopreservation and Artificial Organs, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Yuan Hu, Dongyang Zhang, Tao Yin, Tingting Jiang, Shitao He, Mengzhu Li, Xinyu Yue, Guiying Luo, Fangbiao Tao, Yunxia Cao, Dongmei Ji, Yanli Ji & Chunmei Liang

  7. Anhui Provincial Institute of Translational Medicine, No 81 Meishan Road, Hefei, 230032, Anhui, China

    Yuan Hu, Dongyang Zhang, Tao Yin, Tingting Jiang, Shitao He, Mengzhu Li, Xinyu Yue, Guiying Luo, Fangbiao Tao, Yunxia Cao, Dongmei Ji, Yanli Ji & Chunmei Liang

  8. Department of Ophthalmology, The Second Hospital of Anhui Medical University, No 678 Furong Road, Hefei, 230601, Anhui, China

    Qing Zhang

Authors
  1. Yuan Hu
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  2. Dongyang Zhang
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  3. Qing Zhang
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  4. Tao Yin
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  5. Tingting Jiang
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  6. Shitao He
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  7. Mengzhu Li
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  8. Xinyu Yue
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  9. Guiying Luo
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  10. Fangbiao Tao
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  11. Yunxia Cao
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  12. Dongmei Ji
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  13. Yanli Ji
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  14. Chunmei Liang
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Contributions

Yunxia Cao, Dongmei Ji, Yanli Ji, and Chunmei Liang figured out the conception of this study; Yuan Hu, Dongyang Zhang, Shitao He, and Tingting Jiang tested the blood samples; Mengzhu Li, Xinyu Yue, and Guiying Luo collected the blood samples; Yuan Hu, Dongyang Zhang, Qing Zhang, and Tao Yin analyzed the data and wrote the manuscript; Fangbiao Tao, Chunmei Liang, Yanli Ji, Yunxia Cao, Guiying Luo, and Dongmei Ji offered proposals and provided financial support. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Yunxia Cao, Dongmei Ji, Yanli Ji or Chunmei Liang.

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Hu, Y., Zhang, D., Zhang, Q. et al. Serum Cu, Zn and IL–1β Levels May Predict Fetal Miscarriage Risk After IVF Cycles: A Nested Case–Control Study. Biol Trace Elem Res 201, 5561–5574 (2023). https://doi.org/10.1007/s12011-023-03621-3

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